In a classical series of experiments, Martin and coworkers described the responses of the chronic spinal dog to several classes of opiate compounds (1-2). From these responses he described three types of opiate receptor designated mu, kappa, and sigma. The sigma receptor was proposed to account for the response observed with the experimental drug, SKF10047. This benzomorphan opiate produced an increase in respiratory and heart rate, mydriasis, and a striking behavioral syndrome suggesting a "canine delirium". The sigma-binding site has now been shown to be a unique, non-opioid binding protein present in the central and peripheral nervous system. Compounds that have high affinity for this site such as haloperidol, phenothiazines and even SKF10047, have interactions with other receptors making it difficult to accurately assess the physiologic and pharmacologic role of the sigma-binding site. Recently several high affinity ligands have become available that are selective for the sigma-site. This should make it possible to study the cellular effects of the interaction between sigma-ligands and the binding site. In the present proposal the action of sigma-ligands on single neurons in the locus coeruleus and dorsal raphe will be studied using intracellular recording in brain slices. The action of sigma-ligands on resting properties, spontaneous activity, membrane currents, synaptic potentials and ligand activated currents will be studied. Studies of specific intrinsic and ligand activated membrane currents in isolation will be carried out with the single electrode voltage clamp. As there has been little work done with selective sigma-ligands at the cellular level, this study will lead to an understanding of the cellular actions of this class of psychotomimetic compounds. Equally important, the results may lead to a better understanding of the pathogenesis of and new therapies for schizophrenia.